rs3135507

Positions:

• chr11-116790772-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001371904.1(APOA5):​c.457G>A​(p.Val153Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0387 in 1,613,350 control chromosomes in the GnomAD database, including 2,075 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.056 (332 hom., cov: 34)
  • Exomes 𝑓: 0.037 (1743 hom.)
• Consequence: APOA5 NM_001371904.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.21

Genes affected

APOA5 (HGNC:17288): (apolipoprotein A5) The protein encoded by this gene is an apolipoprotein that plays an important role in regulating the plasma triglyceride levels, a major risk factor for coronary artery disease. It is a component of high density lipoprotein and is highly similar to a rat protein that is upregulated in response to liver injury. Mutations in this gene have been associated with hypertriglyceridemia and hyperlipoproteinemia type 5. This gene is located proximal to the apolipoprotein gene cluster on chromosome 11q23. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016683042).
• BP6: Variant 11-116790772-C-T is Benign according to our data. Variant chr11-116790772-C-T is described in ClinVar as [Benign]. Clinvar id is 496496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-116790772-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOA5	NM_001371904.1	c.457G>A	p.Val153Met	missense_variant	3/3	ENST00000227665.9	NP_001358833.1
APOA5	NM_001166598.2	c.457G>A	p.Val153Met	missense_variant	4/4		NP_001160070.1
APOA5	NM_052968.5	c.457G>A	p.Val153Met	missense_variant	4/4		NP_443200.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOA5	ENST00000227665.9	c.457G>A	p.Val153Met	missense_variant	3/3	1	NM_001371904.1	ENSP00000227665.4
APOA5	ENST00000433069.2	c.457G>A	p.Val153Met	missense_variant	4/4	1		ENSP00000399701.2
APOA5	ENST00000673688.1	c.541G>A	p.Val181Met	missense_variant	3/3			ENSP00000501141.1
APOA5	ENST00000542499.5	c.457G>A	p.Val153Met	missense_variant	4/4	5		ENSP00000445002.1

Frequencies

GnomAD3 genomes AF: 0.0561 AC: 8542 AN: 152156 Hom.: 328 Cov.: 34

Gnomad AFR AF: 0.0901

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0653

Gnomad ASJ AF: 0.0409

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.0696

Gnomad FIN AF: 0.0512

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0287

Gnomad OTH AF: 0.0526

GnomAD3 exomes AF: 0.0503 AC: 12596 AN: 250602 Hom.: 485 AF XY: 0.0500 AC XY: 6782 AN XY: 135656

Gnomad AFR exome AF: 0.0923

Gnomad AMR exome AF: 0.0457

Gnomad ASJ exome AF: 0.0388

Gnomad EAS exome AF: 0.120

Gnomad SAS exome AF: 0.0747

Gnomad FIN exome AF: 0.0493

Gnomad NFE exome AF: 0.0292

Gnomad OTH exome AF: 0.0473

GnomAD4 exome AF: 0.0369 AC: 53912 AN: 1461076 Hom.: 1743 Cov.: 34 AF XY: 0.0383 AC XY: 27822 AN XY: 726908

Gnomad4 AFR exome AF: 0.0908

Gnomad4 AMR exome AF: 0.0471

Gnomad4 ASJ exome AF: 0.0403

Gnomad4 EAS exome AF: 0.178

Gnomad4 SAS exome AF: 0.0763

Gnomad4 FIN exome AF: 0.0479

Gnomad4 NFE exome AF: 0.0255

Gnomad4 OTH exome AF: 0.0457

GnomAD4 genome AF: 0.0562 AC: 8559 AN: 152274 Hom.: 332 Cov.: 34 AF XY: 0.0595 AC XY: 4433 AN XY: 74454

Gnomad4 AFR AF: 0.0901

Gnomad4 AMR AF: 0.0651

Gnomad4 ASJ AF: 0.0409

Gnomad4 EAS AF: 0.129

Gnomad4 SAS AF: 0.0700

Gnomad4 FIN AF: 0.0512

Gnomad4 NFE AF: 0.0287

Gnomad4 OTH AF: 0.0530

Alfa AF: 0.0357 Hom.: 263

Bravo AF: 0.0561

TwinsUK AF: 0.0213 AC: 79

ALSPAC AF: 0.0231 AC: 89

ESP6500AA AF: 0.0841 AC: 370

ESP6500EA AF: 0.0290 AC: 249

ExAC AF: 0.0514 AC: 6237

Asia WGS AF: 0.113 AC: 391 AN: 3478

EpiCase AF: 0.0309

EpiControl AF: 0.0289

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2018	This variant is associated with the following publications: (PMID: 31619059, 30420299, 28548292, 21423763) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 19, 2017	Variant summary: The APOA5 c.457G>A (p.Val153Met) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict benign outcome for this variant. This variant was found in 6280/120674 control chromosomes (262 homozygotes) including ExAC at a frequency of 0.052041, which is approximately 781 times the estimated maximal expected allele frequency of a pathogenic APOA5 variant (0.0000667), suggesting this variant is likely a benign polymorphism. In addition, this variant was not found to confer increased risk of hypertriglyceridemia in a case-control study (Kao_2003). Taken together, this variant is classified as benign. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.28
DANN	Benign	0.96
DEOGEN2	Benign	0.23	T;T;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.72	.;T;T
MetaRNN	Benign	0.0017	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.090	N;N;N
REVEL	Benign	0.079
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.044	B;B;.
Vest4		0.015
MPC		0.54
ClinPred		0.0029	T
GERP RS		-4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.038
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3135507; hg19: chr11-116661488; COSMIC: COSV57063308; COSMIC: COSV57063308;